Smoking is one of the predominant routes of administration of abused drugs such as heroin, phencyclidine, marihuana, tobacco and cocaine base ("crack"). Uptake is more rapid by inhalation than by the intranasal route, and the abuse potential of crack is at least as great as intravenously administered cocaine hydrochloride, if not greater, judging from clinical experience and the limited human literature. Unfortunately, there is a very limited animal literature on self-administration of cocaine base by inhalation, on its pharmacokinetics, or on repetitive use. We have developed technologies for generating aerosol atmospheres of cocaine which are repeatable and are appropriate for quinea pig and monkey. The refinement and of use of this exposure technology with these species will enable the characterization of cocaine self-administration and the pharmacology and toxicity unique to this route of self-administration. These techniques should facilitate subsequent laboratory investigations of cocaine and other drugs subject to abuse by this route, e.g., metham- phetamine hydrochloride. The goals for the next four years of this project include: 1) completing experiments on the aerosol physics of smoked drugs; 2) describing the abuse potential of cocaine base in self-administration sessions of limited duration in laboratory primates, with special attention to tolerance phenomena, and to concentration- and particle-size dependence of the behavior; 3) characterizing the effects of acute inhalation on conditioned behavior and on physiologic indices including: minute ventilation, pulmonary conductance (bronchodilation/constriction), arterial, pulmonary, and pulmonary wedge pressures, and heart rate in laboratory primates; 4) the description of acute and chronic toxicity syndromes, especially those expressed in pulmonary function and respiratory system structure. This will be done by characterizing the effects of acute inhalation on the cardiopulmonary function of guinea pigs: minute ventilation, pulmonary compliance, arterial pressures, heart rate, carbon monoxide diffusing capacity, and enzyme assays on pulmonary lavage fluids that are indicative of lung injury; 5) describing the pharmacokinetics of the agent following acute administration and brief (within--day) regimes of repeated administration. Arterial/venous differences will be described, as will the concentration-dependency of achieved levels by the inhalation and intravenous routes. 6) demonstration of the feasibility of applying these techniques to methamphetamine HCI smoking.